Propylurea-mercury compounds as diuretics



Patented Apr. 21, 1953 PROPYLUREA- MERCURY COMPOUNDS -AS DIURETICS Emanuel Leon Foreman, Alhambra, Calif., assignor to Lakeside Laboratories Inc., a icorporation of Wisconsin N Drawing. Application August 31, 1949, Serial No. 113,493

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This invention relates to propylurea compounds containing mercury and diuretic compositions containing the same.

In various types of heart diseases, particularly congestive heart trouble, the patient. becomes bloated due to sodium in the form of salt and thus water gathering inthetissues. Inorder to relieve this condition, various compositions have been prescribed containing diuretic compounds. These diuretics serve to excrete water and salt from the kidneys and thus from the tissues so that the heart condition is relieved. Many of the former diuretic compounds were aromatic or aliphatic amines or amides, particularly aliphatic amines or amides. Inorganic mercury compoundshave been used as diuretics for many years, but only recently have organic mercury compounds been used. The early organic mercury compounds were amines and amides containing a mercury atom. Most of these prior diuretic compounds, particularly of the mercury type, were dangerous to use as they sometimes caused death by stopping the heart. When they were injected into the veins or the muscles, they sometimes destroyed or at least caused severe irritation of the tissues. This was particularly true where the injection into the muscle accidentally contacted fatty tissues.

The new compounds of this invention have essentially the following structural formula:

wherein R is a member of the class consisting of hydrogen and alkyl, and X is anon-carbon, or inorganic, atom of negative valence, or-a group including such an atom bonded directly to the mercury atom. More specifically, X is either halogen, hydroxyl, oXy-acyl, the residue of an acidic nitrogencompound having a -replaceable hydrogen on the nitrogen atom, or the residue of an alkyl thiol acid wherein the sulfur is bonded directly to the mercury. Those compounds wherein X is either halogen, hydroxyl, oXy-acyl, or the residue of an acidic nitrogen compound having a replaceable hydrogen on the nitrogen atom so that the nitrogen is bonded directly to the mercury atom are disclosed and claimed in th copending application of Ralph L. Rowland, Serial No. 113,494, filed August 31, i949, now abandoned.

The 'alkyl thiol acid used in preparing the thio-mercurated .propylurea compounds has a replaceable hydrogen on the ulfur atom so that 2 the sulfur isbonded directly tothe mercury-atom in the resulting mercurated propylurea compound. The preferred compounds of this invention have the following structural formula:

wherein R and R are each either hydrogen or alkyl. In the preferred cases, R and R" are each an alkyl group containing from 1 to 5 carbon atoms. It is preferred that the alkali metal salt of the acid, such as the sodium or potassium salt, be used as adiuretic as thesesalts are water soluble.

Examples representing the compounds and their "methods of preparation are as follows:

Example 1 0 O 0 Ha 3-carboxymethylthiomercuri-2-methoxy-propylurea To a refluxing solution of 100 g. of allyl urea and 600 ml. of absolute methanol there was added with stirring a suspension of 319 g. of mercuric acetate and 600 ml. of absolute methanal and ml. of g1acia1 acetic acid; complete solution resulted. After 6 hours of refluxing, the solution was cooledand clarified by filtration. To this solution there was added '50 g. of sodium chloride and 240 ml. ofwater. After 'a sh'orttime a heavy white precipitate settled out. This precipitate, which "was 3-chloromercuri-2 methoxy-propylurea, was filtered, "washed and dried. 100 g. of this compound and 400ml. ofwater and g. of 10% sodiumhydroxide was added to a solutionof 25 gyofthioglycolio acid, g. of 10% sodium hydroxidesolution and ml. of water. This solution was clarified by filtration through a bed of filter'aid and 'then acidified with 29 ml. of glacial acetic acid. The white granularsolid which precipitated was filtered, washed and dried (93"gqor 80% yield). The substancemelts at approximately lot-112 C. and on "further heating resolidifies and finally decomposes at 138139 C.

Analysis: Calc: N, 6.62; Hg, 47.5. Found: N. 6.42; Hg, 47.6. The product is readily soluble in water on addition of sodium hydroxide and a 10% solution can be .prepared at physiological pH which, therefore, is suitable for parenteral use.

Example 2 Analysis: Calc.: N, 6.40; Hg, 46.0. N, 6.37; Hg, 45.6.

A solution may be readily prepared with sodium hydroxide.

Found:

Example 3 If in place of the thiolactic acid (a-mercapto propionic acid) of Example 2, there is used 1- mercapto-n-valeric acid, a white solid results in 79% yield, which sinters at 130-135 and decomposes at approximately 165 C.

Analysis: Calc: N, 6.02; Hg, 43.2. Found: N, 6.00; Hg, 43.1.

Example 4 To a warm (70 C.) solution of 85 g. of allyl urea and 500 ml. of absolute n-butanol there was added 271 g. of mercuric acetate in 800 ml. of nbutanol and 50 ml. glacial acetic acid over a period of one hour. After warming an additional /2 hour at approximately 70 C., the solution was permitted to cool and was clarified by filtration. The resulting solution was concentrated and sodium chloride added. There was obtained on further concentration, followed by crystallization from water, 3-ch1oromercuri-2-n-butoxypropylurea. 13 g. of this compound was suspended in 200 cc. of water and 2 molar equivalents of sodium hydroxide (as aqueous solution) was added. To this was then added 2.9 g. of thioglycolic acid. The pH was adjusted to 7.5 and the solution clarified by filtration. The solution was then acidified with acetic acid and the white precipitate filtered, washed well with water and Analysis: Calc: N, 6.02; Hg, 43.1. 6.08; Hg, 42.6.

The use of chloro-mercuri compounds in the Found: N,

4- above examples to make the thiol acid products is only by way of example as it is obvious that other mercuri intermediates can just as easily be used; such as, -HgBr, HgOH, HgOAc, and similar compounds.

The new compounds are used with the ordinary carriers, such as in aqueous solutions of the alkali metal salts, as diuretics and may be injected either intravenously, subcutaneously or intramuscularly. When so injected, there is noted a marked increase in urinary output. This increase ordinarily lasts about five hours after which the output of liquids returns to its normal level. In treating patients having large amounts of water and salt in the tissues. the injections are continued until a constant weight in the patient has been obtained. After this constant weight has been obtained, no more need be given until there is noted a weight increase. The new propylurea derivatives are nontoxic even when given in relatively large amounts and are superior to many other mercury compounds in eliminating a greater amount of liquid in a given time. Because of this, much smaller doses are required.

The foregoing detailed description is given for 'clearness of understanding only and no unnecessary limitations should be understood therefrom, for some modifications will be obvious to those skilled in the art.

I claim: r

1. The new compound having essentially the structural formula:

wherein R is a member of the class consisting of hydrogen and alkyl, and X is a member of the class consisting of the residue of an alkyl thiol acid and the alkali metal salt thereof wherein the sulfur is bonded directly to the mercury atom.

2. The new compound having essentially the structural formula:

wherein R and R are each a member of the class consisting of hydrogen and an alkyl group containing from one to five carbon atoms, and A is a member of the class consisting of hydrogen and alkali metal.

3. The compound of claim 2 wherein R is methyl and R is hydrogen.

4. The compound of claim 2 wherein R is methyl and R is methyl.

5. The compound of claim 2 wherein R, is methyl and R. is propyl.

6. As a diuretic, a pharmaceutical carrier and a thio-mercurated propylurea having the structural formula:

wherein R. is a member of the class consisting of hydrogen and alkyl, and X is a member of the class consisting of the residue of an alkyl thiol acid and the alkali metal salt thereof wherein the sulfur is bonded directly to the mercury atom.

7- As a diuretic, a pharmaceutical carrier and HzN-(-NH-CHz-CH-CHr-Hg-SOHO00A wherein R and R are each a member of the class consisting of hydrogen and an alkyl group containing from one to five carbon atoms, and A is a member of the class consisting of hydrogen and alkali metal.

8. As a diuretic, a pharmaceutical carrier and a thio-mercurated propylurea having the structural formula:

mN-t i-Nn-c Hr-OH-OHz-Hg-SCHC 0 0 A wherein R is methyl, R is methyl, and A is a member of the class consisting of hydrogen and alkali metal.

10. As a diuretic, a pharmaceutical carrier and a thio-mercurated propylurea having the structural formula:

wherein R is methyl, R is propyl, and A is a member of the class consisting of hydrogen and alkali metal.

EMANUEL LEON FOREMAN.

References Cited in the file of this patent UNITED STATES PATENTS Number Name Date 2,208,941 Geiger et a1 June 23, 1940 2,315,817 Ruzicka Apr. 6, 1943 2,576,349 Lehman Nov.. 27, 1951 OTHER REFERENCES Heilbron, Dictionary of Organic Chemistry, volume 1, page 32 (1934).

Lipschitz et al., J. Pharmacology and Experimental Therap., 1944, pages 84-6, 93-4.

New and Nonofiicial Remedies. J. P. Lippincott Company, Philadelphia, Pa., May 1949, pages 316 to 320. 

1. THE NEW COMPOUND HAVING ESSENTIALLY THE STRUCTURAL FORMULA: 